Vertical talus, also called rocker-bottom foot, commonly occurs in patients with multiple congenital abnormalities, such as trisomy 18, trisomy 13, distal arthrogryposis, and myelomeningocele. However, nearly half of all cases of vertical talus occur as an isolated condition with no associated abnormalities. Distinction between isolated vertical talus and syndromic vertical talus is critical because the prognosis and treatment outcomes vary significantly. Though there are many causes of syndromic vertical talus, the genetic basis of isolated vertical talus is poorly understood. Previous studies in our laboratory provided evidence of a major locus for isolated vertical talus, but the causative gene has not yet been identified. To test the hypothesis that a rare genetic variant is responsible for isolated vertical talus, we plan to a study a cohort of patients with familial isolated vertical talus. The subjects for these studies will come from the Washington University Musculoskeletal DNA Database containing more than 3000 patient samples, including 100 patients with vertical talus. Because of the well-known association between chromosomal aneuploidy and vertical talus, we will first evaluate for chromosomal copy number variants (CNVs) in 20 patients with vertical talus, including probands from three autosomal dominant vertical talus families. The detection of small CNVs (<100kb) with this approach previously resulted in our identification of causative genes for clubfoot, a birth defect with many similarities to vertical talus. Using a complementary approach known to be effective for disease gene discovery in mendelian disorders, we will also perform exome sequencing to identify rare coding mutations in probands from three families with isolated familial vertical talus. Finally, mutations in candidate genes will be determined using pooled resequencing in a cohort of patients with vertical talus. The results gained from these experiments will not only advance our understanding of vertical talus, but will allow us to establish the methodologies and infrastructure for future studies of pediatric musculoskeletal disorders. PUBLIC HEALTH RELEVANCE: The goal of this project is to determine the genetic basis of isolated congenital vertical talus, also called rocker- bottom foot. Distinction between isolated vertical talus and syndromic vertical talus is critical because the prognosis and treatment outcomes vary significantly. Genomic copy number analysis will be used to detect microduplications or microdeletions and rare genetic variants will be detected with exome sequencing of probands from three large families with isolated vertical talus. The results gained from these experiments will not only advance our understanding of vertical talus, but will allow us to establish the methodologies and infrastructure for future studies of pediatric musculoskeletal disease.